In connective tissue, the term “ground substance” is the non-cellular components of extracellular matrix. Cells are surrounded by extracellular matrix in tissues, which acts as a support for the cells. Ground substance traditionally does not include collagen but does include all the other proteinaceous components, including proteoglycans, matrix proteins and water. Ground substance is amorphous, gel-like, and is primarily composed of glycosaminoglycans (most notably hyaluronan), proteoglycans, and glycoproteins. The formation of tissue adhesions can best be described as a process of denaturation, and more specifically protein denaturation.
Denaturation is a process in which proteins or nucleic acids lose the tertiary structure and secondary structure which is present in their native state, by application of some external stress or compound such as an acid or base, a concentrated inorganic salt, an organic solvent, exposure to air, or temperature change.
When a surgical procedure is performed external stress is applied to tissue, which can be oxidative, change the ionic equilibrium, create necrotic byproducts, or otherwise increase the entropy of the tissue. If proteins in a living cell are denatured, this results in disruption of cell activity and possibly cell death (which occurs in all surgical procedures). Denatured proteins can exhibit a wide range of characteristics, from loss of solubility to communal aggregation. These two effects tend to create scaffolds on which bridges between living tissues are formed.
Denaturation occurs at different levels of the protein structure. In the quaternary structure denaturation, protein subunits are dissociated and/or the spatial arrangement of protein subunits is disrupted. This can lead to cell death, which promote upregulation of reaction oxygen species as well as providing an environment for microbial proliferation. The tertiary structure denaturation involves the disruption of covalent interactions between amino acid sidechains (such as disulfide bridges between cysteine groups), noncovalent dipoledipole interactions between polar amino acid sidechains, and Van der Waals (induced dipole) interactions between nonpolar amino acid sidechains. In the secondary structure denaturation, proteins lose all regular repeating patterns such as alphahelices and betapleated sheets, and adopt a random coil configuration. This contributes to the higher entropic state associated with chronic inflammation and thick capsule formation.
Primary structure denaturation, such as a sequence of amino acids held together by covalent peptide bonds, is not directly disrupted by denaturation. But the high entropy environment associated with global protein denaturation has been associated with primary structure disruption and pathologies such as cancer.
Most biological substrates lose their biological function when denatured. For example, enzymes lose their activity, because the substrates can no longer bind to the intended active site, and because amino acid residues involved in stabilizing the substrates' transition states are no longer positioned to be able to do so. The denaturing process and the associated loss of activity can be measured using techniques such as dual polarization interferometry.
Unfortunately, almost all antiadhesive materials (gel or sheet) used surgically at present are chaotropic agents. These devices disrupt the structure of macromolecules, and denature macromolecules such as proteins and nucleic acids (e.g. DNA and RNA). Chaotropic solutes increase the entropy of the system by interfering with intramolecular interactions mediated by noncovalent forces such as hydrogen bonds, van der Waals forces, and hydrophobic effects. Hydrophobic effects are primary in establishing the boundaries between tissue layers. When the equilibrium of these forces that are established in vital tissue is disrupted, the “healing” stimulus leads to macroscopic cellular structures that are deleterious to clinical success.
For these reasons it is important that antiadhesion barriers, that are, by their current construction, absorbable, not degrade into byproducts that are chaotropic. Macromolecular structure and function is dependent on the net effect of these forces (for example, protein folding), therefore it follows that an increase in chaotropic solutes precipitated by an implant in a biological system will denature macromolecules, reduce enzymatic activity and induce stress on cells. In particular, tertiary protein folding is dependent on hydrophobic forces from amino acids throughout the sequence of proteins. Chaotropic solutes decrease the net hydrophobic effect of hydrophobic regions because of a disordering of water molecules adjacent to the protein. This solubilizes the hydrophobic region in the solution, thereby denaturing the protein. This is also directly applicable to the hydrophobic region in lipid bilayers; if a critical concentration of a chaotropic solute is reached (in the hydrophobic region of the bilayer) then membrane integrity will be compromised, and the cell (tissue layer) will lyse.
Many implants that degrade into acids form chaotropic salts that are water soluble and exert chaotropic effects via a variety of mechanisms. Whereas chaotropic compounds such as hydroxyl compounds, for example polyethylene glycol, interfere with noncovalent intramolecular forces, salts can have chaotropic properties by shielding charges and preventing the stabilization of salt bridges. Hydrogen bonding is stronger in nonpolar media, so salts, which increase the chemical polarity of the solvent, can also destabilize hydrogen bonding. The loss of hydrogen bonding disassociates the delimiters of tissue layers, promoting translayer bridge formation. In terms of intersurface dynamics, the formation of adhesions is promoted due to insufficient water molecules to effectively solvate the ions resulting from surgical tissue disruption. This can result in iondipole interactions between the salts and hydrogen bonding species which are more favorable than normal hydrogen bonds, which accordingly promote bridging between tissue layers over promotion of tissue layer boundaries.
Accordingly, it is important that an antiadhesion prosthetic that is absorbable not contribute to a chaotropic effect. Granted much of the denaturation due to surgical intervention is due to disruption of tissue layers, cell death and perturbation of the ionic and hydrophobic equilibrium established in living tissue. Thus, a barrier material should be chemically neutral and reestablish the structural aspects of the tissue perturbed by surgical intervention. Since this intervention is intended to be temporary, then the elimination of the barrier material itself must not be chaotropic. This is where most absorbable materials fail. In cases where an implant is intended to disappear to minimize site colonization by endogenous bacteria, and the implant serves a mechanical function, then such chaotropic effects may be acceptable in a risk/benefit analysis. But where a material is specifically implanted for the purpose of reestablishing normal tissue structure, such chemotropic effects may not be ignored.
Additional background information includes the following:
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U.S. Pat. No. 7,026,284 discloses a polyphenol useful as a gene complex, cell adhesion inhibitor or immune tolerogen. The polyphenol of forming the agent is selected from catechin group consisting of epigallocatechingallate, tannic acids, or proantodianisidine, a protein of the protein complex is selected from proteins consisting of animal proteins composed of polypeptide chain of peptidecombined amino acids, vegetative proteins, nucleus proteins, glycogen proteins, lipoproteins and metal proteins, the gene complex comprises by compositing genes by polyphenol catechins in order to introduce genes to cells of animals or human bodies, a cell composed of the cell adhesion inhibitor is selected from cells consisting of an animal cell including a stem cell, skin cell, mucosa cell, hepatocyte, islet cell, neural cell, cartilage cell, endothelial cell, or epidermal cell.
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U.S. Pub. No. 20090208589 discloses new biopolymers which mimic the properties of natural polysaccharides found in vivo. The inventive polysaccharides can be used as viscosupplements, viscoelastics, tissue space fillers, and/or antiadhesive agents.
U.S. Pub. No. 20100160960 discloses hydrogel tissue adhesive is formed by reacting an oxidized polysaccharide with a waterdispersible, multiarm amine in the presence of a polyol additive, which retards the degradation of the hydrogel.
U.S. Pub. No. 20110166089 discloses provide a solution for tissue adhesion prevention and a method for tissue adhesion prevention that are applicable to general surgery and in which covering condition during surgery is stable and convenient. The invention is the solution for tissue adhesion prevention of which the active ingredient is trehalose.
U.S. Pub. No. 20110237542 discloses to a composition for preventing tissue adhesion which comprises a biocompatible hyaluronic acid and a polymer compound. More specifically, the invention is a composition containing hyaluronic acid which has not been modified by a chemical crosslinking agent.
U.S. Pub. No. 20110243883 discloses provides branched polymers which can be used as lubricants or shock absorbers in vivo. For example, the inventive polymers can be used as viscosupplements, viscoelastics, tissue space fillers, and/or antiadhesive agents.